ABSTRACT The goal of this proposal by a multi-disciplinary team at MD Anderson Cancer Center, the University of Texas Southwestern Cancer Center and the University of Pittsburg Cancer Center is to explore approaches based on circulating protein markers and autoantibodies to develop a blood based marker panel to assess risk of harboring or developing small cell lung cancer (SCLC). There are currently several established SCLC protein markers which individually lack sufficient performance for early detection. Additionally, the applicant group has uncovered several protein marker candidates through integrated analyses of mouse models and human SCLC samples. To assess the potential of established and newly discovered candidate markers to yield a combined panel of markers indicative of risk of harboring or developing SCLC, validation studies will be conducted using plasma samples collected up to 5 years prior to a diagnosis of SCLC, from participants in the large European Prospective Investigation into Cancer and Nutrition (EPIC) and the Singapore Chinese Health Study (SCHS) cohorts. Additonally, plasmas collected at the time of diagnosis of SCLC and post-treatment as well as tissue molecular profiles will be interrogated to establish the biological relevance to candidates to SCLC. Two approaches will be implemented to identify antigenic proteins and peptides that induce autoantibodies that can be mined for SCLC early detection. One consisting of Ig bound proteins in plasmas from SCLC cases and another novel approach consists of interrogating whole genome derived peptide arrays for reactivity with aliquots of SCLC plasmas utilized for validation of circulating proteins. The resulting combination of the most promising markers will be further validated using pre-diagnostic SCLC samples and matched controls from the US Prostate Lung Colon and Ovarian (PLCO) cohort. The applicant group has a substantial track record of collaboration and expertise relevant to project objectives, with rigor in experimental design for discovery and validation studies of lung cancer biomarkers.